PROJECT SUMMARY First episodes of major depressive disorder (MDD) typically begin during adolescence. Despite the fact that adolescent-onset MDD is associated with more severe and recurrent episodes of MDD, little work has been done to identify mechanisms underlying depressive relapse or recurrence. Prior work by the candidate has documented differences in functional and structural connectivity involving the anterior cingulate cortex (ACC) between adolescents with MDD and psychiatrically healthy controls; these phenotypes are posited to reflect altered neurodevelopment in key emotion regulation circuitry. We do not yet know, however, whether and how MDD impacts adolescent development of ACC connectivity in a manner that contributes to an increased risk of depressive relapse or recurrence. One mechanism may be the immune system, which activates in response to psychosocial stressors and influences neurotransmitter systems including glutamate, the primary excitatory neurotransmitter in the brain. Basic research indicates that higher levels of pro-inflammatory cytokines leads to overexcitation of glutamatergic neurons to the point of neurotoxicity and, consequently, to reduced neuroplasticity. Further, neuroimaging studies of adult MDD have reported heightened levels of inflammation and altered levels of glutamate in the ACC. These data, combined with growing evidence that ACC connectivity undergoes extensive maturation during adolescence, suggest that heightened inflammation and excessive glutamate may lead to atypical development of this circuitry in adolescents with MDD. The candidate therefore seeks to test the central hypothesis that heightened inflammation acts through glutamate transmission to disrupt typical neurodevelopment of ACC connectivity in adolescents with MDD to increase risk of depressive relapse or recurrence. This K01 will test this model in 60 adolescents with first episodes of MDD assessed longitudinally over 3 time points using an innovative multimodal approach. The candidate will assay peripheral levels of pro-inflammatory cytokines using dried blood spot technology, noninvasively image glutamate and antioxidants in ACC using proton magnetic resonance spectroscopy, and assess neurodevelopmental changes of ACC connectivity using functional (resting-state fMRI) and structural (diffusion MRI) methods. This K01 fills key gaps in our understanding of whether adolescent MDD impacts development of ACC connectivity, how inflammatory and glutamatergic mechanisms underlying MDD-related changes in ACC connectivity contribute to subsequent relapse or recurrence in adolescents with MDD, and whether antioxidants protect against depression recurrence by buffering the effects of inflammation on adolescent development of ACC circuitry. Importantly, the candidate will execute this research in the context of receiving advanced training in stress-related immune biology, causal inference modeling, and developmental psychopathology. Results from this project will culminate in an R01 that aims to identify subtypes/biotypes of adolescent MDD based on clinical course and multimodal characterizations of brain trajectories.